ABSTRACT
Microglia are resident brain macrophages with key roles in development and brain homeostasis. Cytomegalovirus (CMV) readily infects microglia cells, even as a possible primary target of infection in development. Effects of CMV infection on a cellular level in microglia are still unclear; therefore, the aim of this research was to assess the immunometabolic changes of BV-2 microglia cells following the murine cytomegalovirus (MCMV) infection. In light of that aim, we established an in vitro model of ramified BV-2 microglia (BV-2∅FCS, inducible nitric oxide synthase (iNOSlow), arginase-1 (Arg-1high), mannose receptor CD206high, and hypoxia-inducible factor 1α (HIF-1αlow)) to better replicate the in vivo conditions by removing FCS from the cultivation media, while the cells cultivated in 10% FCS DMEM displayed an ameboid morphology (BV-2FCS high, iNOShigh, Arg-1low, CD206low, and HIF-1αhigh). Experiments were performed using both ramified and ameboid microglia, and both of them were permissive to productive viral infection. Our results indicate that MCMV significantly alters the immunometabolic phenotypic properties of BV-2 microglia cells through the manipulation of iNOS and Arg-1 expression patterns, along with an induction of a glycolytic shift in the infected cell cultures.
Subject(s)
Arginase/immunology , Herpesviridae Infections/immunology , Host-Pathogen Interactions/immunology , Microglia/virology , Muromegalovirus/genetics , Nitric Oxide Synthase Type II/immunology , Animals , Arginase/genetics , Cell Line , Culture Media, Serum-Free/pharmacology , Embryo, Mammalian , Fibroblasts/immunology , Fibroblasts/virology , Gene Expression Regulation , Herpesviridae Infections/genetics , Herpesviridae Infections/virology , Host-Pathogen Interactions/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/deficiency , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/immunology , Lectins, C-Type/deficiency , Lectins, C-Type/genetics , Lectins, C-Type/immunology , Mannose Receptor , Mannose-Binding Lectins/deficiency , Mannose-Binding Lectins/genetics , Mannose-Binding Lectins/immunology , Mice , Mice, Inbred BALB C , Microglia/immunology , Models, Biological , Muromegalovirus/growth & development , Muromegalovirus/metabolism , Nitric Oxide Synthase Type II/deficiency , Nitric Oxide Synthase Type II/genetics , Primary Cell Culture , Receptors, Cell Surface/deficiency , Receptors, Cell Surface/genetics , Receptors, Cell Surface/immunology , Signal TransductionABSTRACT
Cortical gray matter loss in schizophrenia remains a great therapeutic difficulty. Each psychotic episode causes irreversible cortical gray matter loss, that causes the patients to never regain their previous state of functioning. Microglial cells are part of the innate immune system and their functions, among others, include phagocytosis and release of neurotrophic factors. They have a key impact on developmental and plasticity-induced removal of neuronal precursors, live-but-stressed neurons and synapses, while also stimulating synaptic growth and development. We hypothesize that microglia are the culprit for the cortical gray matter loss in schizophrenia through abnormal synaptic pruning, phagocytosis of stressed neurons and lacking neurotrophic factor release. Furthermore, we propose a research that could validate the hypotheses using serum samples of first-episode early-onset patients. By measuring the serum levels of milk fat globule-EGF factor 8 (MFG-E8), subcomponent in the classical pathway of complement activation (C1q), brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6) and interleukin-10 (IL-10), we could gain an insight into the state of microglial activation during various stages of the disease. If this hypothesis is valid, new targeted drugs could be developed in order to reduce the deterioration of cortical gray matter, thereby possibly improving negative symptoms and cognitive deficits.
